ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.

Milica Milivojevic,Pamela Schnupf,Anne-Sophie Dangeard,Julie Guignot,Cécile Arrieumerlou,Mario Emmenlauer,Christoph Alexander Kasper,Claudine Pique,Therese Tschon,Dana J Philpott

doi:10.1371/journal.ppat.1006224

Abstract

During infection by invasive bacteria, epithelial cells contribute to innate immunity via the local secretion of inflammatory cytokines. These are directly produced by infected cells or by uninfected bystanders via connexin-dependent cell-cell communication. However, the cellular pathways underlying this process remain largely unknown. Here we perform a genome-wide RNA interference screen and identify TIFA and TRAF6 as central players of Shigella flexneri and Salmonella typhimurium-induced interleukin-8 expression. We show that threonine 9 and the forkhead-associated domain of TIFA are necessary for the oligomerization of TIFA in both infected and bystander cells. Subsequently, this process triggers TRAF6 oligomerization and NF-κB activation. We demonstrate that TIFA/TRAF6-dependent cytokine expression is induced by the bacterial metabolite heptose-1,7-bisphosphate (HBP). In addition, we identify alpha-kinase 1 (ALPK1) as the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to infection with S. flexneri and S. typhimurium but also to Neisseria meningitidis. Altogether, these results clearly show that ALPK1 is a master regulator of innate immunity against both invasive and extracellular gram-negative bacteria.

Highlights

Intestinal epithelial cells (IECs) are not considered to be professional immune cells
We show that threonine 9 (T9) and the forkhead-associated domain (FHA domain) of TIFA are both important for the oligomerization of TIFA occurring in infected and bystander cells
We demonstrate that TIFA/TRAF6-dependent IL-8 expression is triggered by the bacterial metabolite heptose-1,7-bisphosphate (HBP)

Summary

Introduction

Intestinal epithelial cells (IECs) are not considered to be professional immune cells They play an important role in immuno-surveillance and contribute to the initial phase of inflammation after infection by invasive bacteria or viruses. They can sense the presence of pathogens and orchestrate, together with resident macrophages, the recruitment of immune cells to sites of infection. IECs sense highly conserved pathogen-associated molecular patterns (PAMPs) via pathogen recognition receptors (PRRs) including Toll-like (TLRs) and NOD-like receptors (NLRs). They detect cellular stress-induced danger-associated molecular patterns (DAMPs) produced during infection. All these sensing mechanisms result in complex signal transduction cascades regulating the expression of proinflammatory genes coding for cytokines, chemokines and antimicrobial peptides

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